More than 300 Americans die from prolonged VF in the prehospital setting each day. Although defibrillation is the treatment of choice for VF, defibrillation from prolonged VF usually results in non-perfusing rhythms (asystole or pulseless electrical activity). Successful resuscitation after defibrillation into a pulseless rhythm is rare after prolonged VF in the prehospital setting. The objective of this proposal is to develop a new strategy for the treatment of prolonged prehospital VF cardiac arrest. Prompt post-countershock CPR is effective for resuscitation of animals with non-perfusing rhythms after prolonged VF, but is rarely provided in the prehospital setting. Automated external defibrillators (AEDs) are generally the first available defibrillator, and the delays from the post-countershock automated electrocardiographic rhythm analysis and shock advisory, coupled with delays due to clinical assessment, preclude prompt post-countershock CPR. These AED-associated delays interfere with successful resuscitation in animal models and in clinical prehospital care. Our hypothesis is that prompt restoration of blood flow immediately after the first countershock will improve outcome from prolonged VF. To test our hypothesis, we propose to pursue the following specific aims. Aim #1 is to determine a "best" post-countershock blood flow optimizing technique by evaluating: a) single shocks vs series of up to 3 stacked shocks, b) immediate post-countershock CPR for 1 vs 3 minutes without prior clinical evaluation or rhythm assessment, and c) chest compressions alone vs chest compressions plus rescue breathing. The primary endpoint will be successful initial resuscitation. Post-resuscitation myocardial function, 24-hour survival, neurological status, and initial post-countershock myocardial and systemic metabolic status will also be evaluated. Aim #2 is to compare the "best" post-countershock blood flow optimizing technique versus standard care (i.e., stacked shocks, followed by chest compressions plus rescue breathing commencing 1 minute after the first countershock). Aim #3 is to compare the "best" post-countershock blood flow optimizing technique versus standard care, using a swine model with acute myocardial infarction. The primary endpoint for Aims #2 and #3 is 48-hour survival with good neurological outcome. The results of this study should translate into a more successful new therapeutic strategy to restore heart function and preserve neurological function after prolonged VF.